1. Field of the Invention
This invention relates to methods and devices for administration of substances into at least two compartments of skin for systemic absorption and improved pharmacokinetics.
2. Background Information
The importance of efficiently and safely administering pharmaceutical substances such as diagnostic agents and drugs has long been recognized. Although an important consideration for all pharmaceutical substances, obtaining adequate bioavailability of large molecules such as proteins that have arisen out of the biotechnology industry has recently highlighted this need to obtain efficient and reproducible absorption (Cleland et al., Curr. Opin. Biotechnol. 12: 212-219, 2001). The use of conventional needles has long provided one approach for delivering pharmaceutical substances to humans and animals by administration through the skin. Considerable effort has been made to achieve reproducible and efficacious delivery through the skin while improving the ease of injection and reducing patient apprehension and/or pain associated with conventional needles. Furthermore, certain delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin. However, such delivery systems do not reproducibly breach the skin barriers or deliver the pharmaceutical substance to a given depth below the surface of the skin and consequently, clinical results can be variable. Thus, mechanical breach of the stratum corneum such as with needles, is believed to provide the most reproducible method of administration of substances through the surface of the skin, and to provide control and reliability in placement of administered substances.
Approaches for delivering substances beneath the surface of the skin include subcutaneous, intramuscular or intravenous routes of administration of which, intramuscular (IM) and subcutaneous (SC) injections have been the most commonly used.
Anatomically, the outer surface of the body is made up of two major tissue layers, an outer epidermis and an underlying dermis, which together constitute the skin (for review, see Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. A. Goldsmith, Ed., Oxford University Press, New York, 1991). The epidermis is subdivided into five layers or strata of a total thickness of between 75 and 150 μm. Beneath the epidermis lies the dermis, which contains two layers, an outermost portion referred to as the papillary dermis and a deeper layer referred to as the reticular dermis. The papillary dermis contains vast microcirculatory blood and lymphatic plexuses. In contrast, the reticular dermis is relatively acellular and avascular and made up of dense collagenous and elastic connective tissue. Beneath the epidermis and dermis is the subcutaneous tissue, also referred to as the hypodermis, which is composed of connective tissue and fatty tissue. Muscle tissue lies beneath the subcutaneous tissue.
As noted above, both the subcutaneous tissue and muscle tissue have been commonly used as sites for administration of pharmaceutical substances. The dermis, however, has rarely been targeted as a site for administration of substances. This may be due, at least in part, to the difficulty of precise needle placement into the intradermal space. Furthermore, although the dermis, and in particular the papillary dermis, has been known to have a high degree of vascularity, it has not heretofore been appreciated that one could take advantage of this high degree of vascularity to obtain an improved absorption profile for administered substances compared to subcutaneous administration. This is because small drug molecules are typically rapidly absorbed after administration into the subcutaneous tissue which has been far more easily and predictably targeted than the dermis has been. On the other hand, large molecules such as proteins and large polypeptides are typically not well absorbed through the capillary epithelium regardless of the degree of vascularity so that one would not have expected to achieve a significant absorption advantage over subcutaneous administration by the more difficult to achieve intradermal administration even for large molecules.
Numerous methods and devices have been proposed to enhance the permeability of the skin and to increase the diffusion of various drugs through the skin to be utilized by the body.
Devices for Skin-Based Delivery
Recent advancements in microelectrical mechanical systems (MEMS)-based fabrication technologies have permitted the development of small needle-like devices that overcome this tissue barrier and provide direct mechanical access to the epidermis and upper dermal tissue. Minimally-invasive safe delivery is accomplished by limiting the depth of penetration to the outer 10 μm to 2 mm, thus avoiding the nerve endings and blood vessels found deeper within the skin. Micro-cannula- and microneedle-based methodology and devices are described in U.S. application Ser. No. 606,909, filed Jun. 29, 2000. Standard steel cannula can also be used for intra-dermal delivery using devices and methods as described in U.S. Ser. No. 417,671, filed Oct. 14, 1999. These methods and devices include the delivery of substances through narrow gauge (30 G or narrower) “micro-cannula” with a limited depth of penetration (typically ranging from 10 μm to 2 mm), as defined by the total length of the cannula or the total length of the cannula that is exposed beyond a depth-limiting hub feature.
The devices for disrupting the stratum corneum include microabraders and microsize needles or blades having a length to penetrate and substantially pierce the stratum corneum. Other devices include microabraders and microsize needles or blades having a length to penetrate the stratum corneum without substantially piercing the stratum corneum. Microneedles include structures with a diameter equivalent to or smaller than about 30 gauge, typically about 30-50 gauge when such structures are cylindrical in nature. Non-cylindrical structures encompassed by the term microneedles would therefore be of comparable diameter and include pyramidal, rectangular, octagonal, wedge, and other suitable geometrical shapes. Examples of these devices are disclosed in U.S. Pat. No. 5,879,326 to Godshall et al.; U.S. Pat. No. 5,250,023 to Lee et al., and WO 97/48440.
Pharmacokinetics
Comparative studies have shown that the pharmacokinetic (PK) profiles of medicaments delivered to particular compartments of skin and depths within those compartments can vary dramatically. For example, pharmacokinetics for certain classes of medicaments can be improved by intradermal delivery (see, e.g., U.S. application Ser. No. 606,909 filed Jun. 29, 2000 and U.S. application Ser. No. 893,746 filed Jun. 29, 2001 (Published Jul. 18, 2002 as publication no. 20020095134)). To date the focus of altering PK through intradermal delivery has been on increased onset of effect and enhanced bioavailability relative to standard SC dosing.